Cephalosporins are a group of antibiotics derived from Cephalosporium Acremonium, a fungus first isolated from sand near the Sardinia sea shore by Brotju in 1948. Naturally occuring cephalosporins, such as cephalosporin P, N, and C, have been discovered in C. Acremonium culture medium and were found to have bacteriostatic activities against Staphyllococcos aureus.
Among the three natural cephalosporins, cephalosporin C closely resembles penicillin both in terms of having a fused beta-lactam ring and having a broad antibiotic activity, however its very weak clinical effect has limited its use as an antibiotic. Accordingly, much research has been devoted towards the synthesis of semi-synthetic cephalosporin analogs with the goal of creating useful semi-synthetic, broad spectrum antibiotics having bacteriocidal or bacteriostatic activity against Gram positive and Gram negative bacteria.
A number of synthetic routes for preparing semisynthetic cephalosporin antibiotics, starting from 7-aminocephalosporanic acid (7-ACA), have been reported. For example, the D-2-amino adipic acid side chain of cephalosporin C can be hydrolyzed to yield 7-ACA as shown in the following equation ##STR1##
Many kinds of functional groups can be introduced into the 7-and 3-positions of 7-ACA, thereby a variety of semisynthetic cephalosporanic antibiotics can be produced by such chemical modification.
In addition, if the substituent on C3 of 7-ACA were modified to CH.sub.3 -group, many antibiotics suitable for oral administration could thus be synthesized. The acetoxy group on CH.sub.3 of 7-ACA can be removed to form 7-aminodesacetoxy cephalosporanic acid (7-ADCA), an intermediate between cephem and penam. That is, 7-ADCA can be produced by reduction of 7-ACA derivatives or by oxidation of 6-APA derivatives.
In one method, 7-ADCA was prepared by reduction of 7-ACA as shown in the following equation: ##STR2##
The product resulting from this reaction, however, is costly due to the use of expensive 7-ACA as starting material and nobel metal as catalyst.
Another method for the preparation of 7-ACDA is based on ring expansion of penicillin starting materials. Its synthetic route is as follows: ##STR3##
Pencillin G (R=--CH.sub.2 --.phi.) or penicillin V (R=--CH.sub.2 --O--.phi.) can be oxidized in water with periodic acid or peracetic acid as oxidant to form its corresponding sulfoxide. The sulfoxide is esterified to protect its carboxylic group, then heated in the presence of an acid catalyst to carry out the ring enlargement reaction. The product is then hydrolyzed to remove the protecting group and deacetylated by chemical or enzymatic methods to produce 7-ADCA.
The aforementioned process comprises oxidation, esterification, ring enlargement, hydrolysis, and deacetylation. Among which, the reagent selected for the esterification can affect not only the facility and yields of the esterification and hydrolysis reactions, but also influences the selectivity of ring enlargement reaction. In commercialized processes, the protecting ester groups used include trichloroethyl (U.S. Pat. No. 3,725,397), dibenzylmethyl (U.S. Pat. No. 3,658,799), and trimethylsilyl (U.S. Pat. No. 3,944,545) groups.
When alkylsilylating agents are employed, both esterification and hydrolysis can be carried out easily and produce high yields of the product. Furthermore, when alkylsilylating agent is used as dehydrating agent in the ring enlargement reaction, under the strong interaction between alkylsilylating agent and water, esterification, ring enlargement reaction and hydrolysis can be readily accomplished in one pot.
For the ring enlargement reaction, the presence of chloride ion or minor changes in the acidity or basicity of the reaction mixture can significantly affect the yield of the product. Similarly, different kinds of alkylsilylating agents and compositions of alkylsilylated products can produce various effects as well.
To avoid the effect of acidity and basicity and of chloride ion on the labile alkylsilylated ester product, neutral alkylsilylating agents have been employed in the ring enlargement reaction. For example, U.S. Pat. No. 4,003,894) describes the use of N,O-bis (trimethyl silyl) acetamide, or N,N'-bis (trimethyl silyl) urea which produce relatively good results. These reagents, however, are very costly. Moreover, in order to prevent destruction of the alkylsilylated penicillin ester by water produced in the ring enlargement reaction, excess amounts of the alkylsilylating agent, in amounts of three to four times the mole equivalent of the penicillin ester, are required. Thus, the cost of the alkylsilylating agent dominates the production cost of 7-ADCA.
Accordingly, there is a need in the art for a commercially useful method of producing 7-ADCA in high yields and which avoids the use of excessive amounts of costly neutral alkylsilylating agents.